Tuberculosis remains a leading infectious cause of death worldwide and infects about one-third of the world's population. The existing TB treatment needs a cocktail of three or four different drugs (first-line drug regimen such as isoniazide, pyrazinamide, and rifampin and several second line drug regimen including ethionamide, para-aminosalicylic acid, kanamycin, amikacin, capreomycin, ciprofloxacin, streptomycin, etc.) and is exceedingly lengthy therapy which has lead to the emergence of multidrug resistant TB (MDR-TB) and extensively drug resistant TB (XDR-TB), which has further complicated the world situation [BemerMelchior, P.; Bryskier, A.; Drugeon, H. B. J. Antimicrob. Chemother. 2000, 46, 571; Abubaker, J.; Schraufnagel, D. J. Am. Med. Assoc. 2000, 283, 54; Dye. C.; Scheele, S.; Dolin, P.; Pathania, V.; Raviglione, M. C. J. Am. Med. Assoc. 1999, 282, 677]. The World Health Organization (WHO) has estimated that if the present conditions remain unchanged, more than 30 million lives will be claimed by TB between 2000 and 2020. TB has also been declared as a global health emergency because of the increase in secondary infections and/or coinfection in cancer and immunocompromised patients (such as those infected with human immunodeficiency virus). Therefore, the current situation necessitates the development of new and potent anti-tuberculosis agents with low toxicity profiles which are effective against both drug-susceptible and drug-resistant strains of M. tuberculosis along with being capable of shortening the current duration of therapy and can be used in conjunction with drugs used for treatment of secondary infections such as cancer and HIV. After four decades, US-FDA recently approved TMC-207 {bedaquiline, a diarylquinone derivative developed by Johnson & Johnson (J&J)}, first drug against MDR-TB which works by inhibiting ATP-synthase and approval of TMC-207 is being seen as a starting point for a new era of TB treatment [Edney, Anna (Dec. 31, 2012). “J&J Sirturo Wins FDA Approval to Treat Drug-Resistant TB”. Bloomberg. Retrieved 2013-01-01].
In the last decade, nitroimidazole skelton (A, FIG. 1) developed great interest among the researchers of academic and industrial fields, which lead to the discovery of two anti-TB clinical candidates namely PA-824 (B, FIG. 1), a nitroimidazopyran derivative, developed by PathoGenesis Corporation [US2006087358A (2000); Stover, C. K.; Warrener, P.; VanDevanter, D. R.; Sherman, D. R.; Arain, T. M.; Michael H. Langhorne, M. H.; Anderson, S. W.; Towell, J. A.; Ying Yuan, Y.; McMurray, D. N.; Kreiswirth, B. N.; Barryk, C. E.; Baker, W. R. Nature 2000, 405, 962] and OPC-67683 (C, FIG. 1), a 6-nitro-2,3-dihydronitroimidazooxazole derivative, developed by Otsuka Pharmaceuticals Co. Ltd. [WO2004033463A1 (2004), EP1555267A1 (2005), WO2007013477A1 (2007); Sasaki, H.; Haraguchi, Y.; Itotani, M.; Kuroda, H.; Hashizume, H.; Tomishige, T.; Kawasaki, M.; Matsumoto, M.; Komatsu, M.; Tsubouchi, H. J. Med. Chem. 2006, 49, 7854]. Initially, researchers at Ciba-Geigy India started a programmne on the nitroimidazole skeleton (A, FIG. 1) to discover novel anti-tuberculosis agent and in 1989 reported a bicyclic nitroimidazooxazole (CGI 17341, D, FIG. 1) which possessed potent in vitro activity and in vivo anti-TB activity [Nagarajan, K.; Shankar, R. G.; Rajappa, S.; Shenoy, S. J.; Costa-Pereira, R. Eur. J. Med. Chem. 1989, 24, 631] but later discontinued due to mutagenic property [Ashtekar, D. R.; Costa-Perira, R.; Nagrajan, K.; Vishvanathan, N.; Bhatt, A. D.; Rittel, W. Antimicrob. Agents Chemother. 1993, 37, 183].
In present invention, new generation anti-TB molecules based on 6-nitro-2,3-dihydronitroimidazooxazoles as inherent component with triazoles, tetrazoles, isoxazoles, urea and sulphonamide functionalities are designed that may fulfill the challenges of anti-tuberculosis drug discovery such as good stability under various conditions, high oral bioavailability, good elimination half-life, free from genotoxicity/mutagenicity and hERG liabilities and absence of drug-drug interactions which is critical in combination treatments.